TGF-β-FOXO signalling maintains leukaemia-initiating cells in chronic myeloid leukaemia
TGF-β-FOXO signalling maintains leukaemia-initiating cells in chronic myeloid leukaemia
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DOI：
10.1038/nature08734
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发表时间：
2010-02-04
期刊：
影响因子：
64.8
通讯作者：
Hirao, Atsushi
中科院分区：
文献类型：
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作者：
Naka, Kazuhito;Hoshii, Takayuki;Hirao, Atsushi
慢性髓系白血病(CML)是由一种明确的遗传异常引起的，该异常产生BCR-ABL，一种结构性活性酪氨酸激酶(1)。人们普遍认为，BCR-ABL激活Akt信号通路，抑制叉头O转录因子(FOXO)，支持CML细胞的增殖或抑制其凋亡(2-4)。虽然酪氨酸激酶抑制剂伊马替尼的使用是慢性粒细胞白血病治疗的一项突破，但伊马替尼并不会耗尽导致慢性粒细胞白血病复发的白血病启动细胞(LIC)(5-8)。在这里，使用同基因移植系统和CML样骨髓增殖性疾病小鼠模型，我们表明Foxo3a在CML LIC的维持中具有重要作用。我们发现，在LIC群体中，具有Foxo3a核定位和Akt磷酸化降低的细胞丰富。连续移植Foxo3a(+/+)和Foxo3a(-/-)小鼠的LICs表明，Foxo3a缺乏症使LICs的致病能力显著降低。此外，我们发现转化生长因子-β是LIC中Akt激活的关键调节因子，并控制Foxo3a的本地化。联合应用转化生长因子-β抑制、Foxo3a缺乏症和伊马替尼治疗可有效去除体内CML。此外，用转化生长因子-β抑制剂处理人CML LIC会削弱它们的体外集落形成能力。我们的结果证明了转化生长因子-β-FOXO通路在维持LIC中的关键作用，并加强了我们对体内特定维持CML LIC的机制的理解。
Chronic myeloid leukaemia (CML) is caused by a defined genetic abnormality that generates BCR-ABL, a constitutively active tyrosine kinase(1). It is widely believed that BCR-ABL activates Akt signalling that suppresses the forkhead O transcription factors (FOXO), supporting the proliferation or inhibiting the apoptosis of CML cells(2-4). Although the use of the tyrosine kinase inhibitor imatinib is a breakthrough for CML therapy, imatinib does not deplete the leukaemia-initiating cells (LICs) that drive the recurrence of CML(5-8). Here, using a syngeneic transplantation system and a CML-like myeloproliferative disease mouse model, we show that Foxo3a has an essential role in the maintenance of CML LICs. We find that cells with nuclear localization of Foxo3a and decreased Akt phosphorylation are enriched in the LIC population. Serial transplantation of LICs generated from Foxo3a(+/+) and Foxo3a(-/-) mice shows that the ability of LICs to cause disease is significantly decreased by Foxo3a deficiency. Furthermore, we find that TGF-beta is a critical regulator of Akt activation in LICs and controls Foxo3a localization. A combination of TGF-beta inhibition, Foxo3a deficiency and imatinib treatment led to efficient depletion of CML in vivo. Furthermore, the treatment of human CML LICs with a TGF-beta inhibitor impaired their colony-forming ability in vitro. Our results demonstrate a critical role for the TGF-beta-FOXO pathway in the maintenance of LICs, and strengthen our understanding of the mechanisms that specifically maintain CML LICs in vivo.